Chlamydia trachomatis is a sexually transmitted bacterium of public health concerns because it causes morbidity and socioeconomic burdens, such as infertility, ectopic pregnancy and chronic abdominal pain. Despite many years of vaccine development efforts, there is no vaccine against C. trachomatis, which probably stems in part from ineffective delivery systems or formulations that do not bolster immune responses to achieve long-lasting protective immunity. Therefore it is essential to explore other delivery systems that may effectively enhance the vaccine efficacy. Biodegradable nanoparticles offer attractive alternatives as adjuvants and delivery systems because they effectively enhance immunogenicity by providing controlled and sustained release of antigens to the immune system. We have developed two novel C. trachomatis nanovaccines employing PLGA (Poly D, L-lactic-co-glycolic acid) and PLA-PEG (Poly D, L-lactic acid-Polyethylene glycol), respectively as delivery systems for its recombinant major outer membrane protein (rMOMP) and peptide derivative (named M278). The named PLGA-rMOMP and PLA-PEG-M278 nanovaccines were immunogenic, immune-potentiating, and triggered profound C. trachomatis correlative Th1 protective immune responses in mice. Our goals are to investigate the molecular mechanisms by which nanovaccines interact with antigen presenting cells for T cell activation; the T and B cell-mediated effectors of the Th1 correlative protective immune responses, and whether the immune correlates can provide complete protective immunity against C. trachomatis infection in mice. Two specific aims are proposed to accomplish our goals. In SA1 we will assess the interaction of nanovaccines with antigen presenting cells for receptor-mediated recognition, cellular uptake, processing, and T cell subsets activation to produce Th1 protective immune responses. In SA2, we will immunize mice with nanovaccines to measure Th1 cellular and humoral protective immune correlates and evaluate whether these correlates can provide short- and long-term protective immunity against C. trachomatis infection in mice. Achieving this proposal's goals would positively impact C. trachomatis vaccine research and improve our efforts toward developing an anti-Chlamydia vaccine.